Denovo Biopharma LLC (Denovo), a pioneer in applying precision medicine to the development of innovative drugs, today announced positive results for its biomarker‑guided Phase 2b clinical trial (ENLIGHTEN) designed to assess the efficacy and safety of DB104 (liafensine) in patients with treatment-resistant depression (TRD).

More than 23 million people in the U.S. alone suffer from major depressive disorder (MDD). Over 30% do not benefit from currently available antidepressants and are diagnosed with TRD. TRD remains a highly unmet medical need indication as there are few approved pharmacological agents for TRD and overall, outcomes remain poor.

Liafensine is a first‑in‑class triple reuptake inhibitor targeting transporters for serotonin, norepinephrine, and dopamine. Using its unique big data based Denovo Genomic Marker (DGM™) biomarker platform, Denovo discovered a novel genetic biomarker, termed DGM4™, which was hypothesized to predict liafensine’s efficacy in TRD patients.

ENLIGHTEN, a DGM4 biomarker‑guided, randomized, double‑blind, placebo‑controlled global Phase 2b trial designed to validate the biomarker hypothesis, enrolled 197 patients with TRD. DGM4‑positive TRD patients who received liafensine demonstrated highly significant improvements over the 6‑week treatment period compared to those who received placebo. The primary endpoint was met: the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline for liafensine demonstrated a 4.4‑point improvement over placebo (p = 0.0056). All secondary endpoints were also met: changes in both the Clinical Global Impressions Scale‑Severity (CGI‑S) and the Sheehan Disability Scale (SDS) change from baseline for liafensine showed an approximately 36% improvement over placebo; additionally, the Clinical Global Impressions Scale-Improvement (CGI‑I) was 2.3 for liafensine, a 0.6‑point improvement over placebo (p = 0.0026). Liafensine was well tolerated and demonstrated an excellent safety profile consistent with previous clinical trials which included more than 2,200 subjects.

“I am truly excited about these positive results in TRD, which is one of the toughest central nervous system (CNS) diseases to treat. The results are remarkable as we have seen a greater than 40% improvement in depression symptoms, which is a greater magnitude than some approved drugs in current use.” said Matthew Spear, Chief Medical Officer and Chief Development Officer at Denovo. “It represents a breakthrough in using precision medicine for CNS diseases, as it is the first time a genetic biomarker has been used to enrich responders in TRD patients, which is the key to its benefit.”

“The success of the ENLIGHTEN trial is a transformative milestone for Denovo as it validates the innovative biomarker approach that Denovo uses to advance otherwise failed late‑stage drugs,” said Wen Luo, Chief Executive Officer and Chief Scientific Officer of Denovo. “We have started the process of identifying a global partner to expedite further development of liafensine towards the market to benefit millions of TRD patients around the world. We are also working on biomarkers for additional drug candidates in other diseases with high unmet needs. Overall, this marks the beginning of a new era of a more efficient way of developing innovative therapies for CNS diseases.”